Many plant materials are antioxidative, but have limited effect in vivo because of their poor solubility and low dissolution velocity. Examples are the antioxidants rutin and resveratrol (see Mattivi, F, Vrhovsek, U, Masuero, D, Trainotti, D, Differences in the amount and structure of extractable skin and seed tannins amongst red grape varieties; Australian Journal of Grape and Wine Research 2009; 15: 27-35; Bertelli, A A, Gozzini, A, Stradi, R, Stella, S, Bertelli, A; Stability of resveratrol over time and in the various stages of grape transformation. Drugs Exp Clin Res 1998; 24: 207-11), obtained from plants and being present in food and drinks (e.g. resveratrol in red wines). Therefore, they are not suitable for effective products, e.g. nutraceuticals or as drug in supportive cancer therapy. However it is described in the literature that nanonization improves their in vivo efficiency. For example, the dermal activity of rutin could be increased by a factor 1,000 comparing rutin nanocrystals with a water soluble derivative (WO2008/058755).
Antioxidants are also present in the peels of grapes (see Mattivi, F, Vrhovsek, U, Masuero, D, Trainotti, D, Differences in the amount and structure of extractable skin and seed tannins amongst red grape varieties; Australian Journal of Grape and Wine Research 2009; 15: 27-35; Bertelli, A A, Gozzini, A, Stradi, R, Stella, S, Bertelli, A; Stability of resveratrol over time and in the various stages of grape transformation. Drugs Exp Clin Res 1998; 24: 207-11). However, due to their poor solubility, these antioxidants cannot be exploited in products. The peels are therefore nowadays normally discarded. One aim of the present invention was therefore to formulate nanocrystals or amorphous nanoparticles of actives, e.g. from peels of grapes, as nanosized material, and to develop a process for the cost-effective production thereof.
Nanosized materials (having a size in the range of from 1 nm to 1,000 nm, referred to herein as the nanorange) have particular physico-chemical properties. These properties can be exploited for the improved delivery of poorly soluble actives in pharma (drugs, diagnostics), cosmetics (cosmetic actives) and nutrition (e.g. nutraceuticals) technology. Amongst these properties are increased saturation solubility, increased dissolution velocity, adhesiveness to surfaces/membranes in the body, and the small size itself allowing for example to use certain administration routes, e.g. intravenous injection. The particles can be crystalline (so called nanocrystals), or can be amorphous (so called amorphous nanoparticles), or can be a mixture of crystalline and amorphous (partially crystalline) particles. An overview about these nanosized materials is given in the reviews by C. M. Keck and R. H. Müller (Müller, R. H., C. M. Keck, Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol, 2004. 113(1-3): p. 151-70.; Keck, C M, Müller, R H, Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 2006; 62: 3-16.; Müller, R H, Gohla, S, Keck, C M, State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm 2011; 78: 1-9). The nanosized materials are typically produced in a liquid by wet milling. A suspension of nanosized material in a liquid is called nanosuspension.
Increased saturation solubility Cs and increased dissolution velocity dc/dt enhance the oral bioavailability of poorly soluble drugs of class II of the biopharmaceutical classification system (BCS). Absorption of poorly soluble nutrients is also increased. Delivery of nanosized actives to the skin increases the penetration into the skin, yielding an increase in effect by up to a factor of 500 (Keck, C, Kobierski, S, Mauludin, R, Müller, R H, Second generation of drug nanocrystals for delivery of poorly soluble drugs: smartCrystals technology, Dosis 2, 126-130, 2008). Therefore these nanosized materials are of high commercial interest.
There are basically two approaches to create these nanosized materials, the “bottom-up” technologies and the “top-down” technologies. In the bottom-up technologies (e.g. precipitation), the nanosized material is obtained by precipitation. The active is dissolved in a solvent, the solvent is added to a non-solvent that is miscible with the solvent, and the particles precipitate. Depending on the precipitation conditions, either crystalline particles are obtained (e.g. so called “hydrosols” (GB Patent 2200048) or amorphous nanoparticles (e.g. product NanoMorph by the company Soliqs, Ludwigshafen, Knollstraβe, Germany (U.S. Pat. No. 6,494,924 B1)). There are several disadvantages of the bottom-up technologies:    1. The use of organic solvents which need to be costly removed.    2. Potential solvent residues contaminating the product.    3. The process is costly, due to the use of large solvent quantities in case of very poorly soluble drugs.
For these reasons there are no or very few pharmaceutical products on the market that have been produced using bottom-up technologies.
Industrially feasible are the top-down technologies (e.g. bead milling, high pressure homogenization). Micrometer-sized material is reduced in size to the nanometer range by milling processes, in general wet milling. The major approaches are wet milling in bead/pearl mills (e.g. NanoCrystal product by the company élan, USA) or wet milling by high pressure homogenization. A review of these processes is given by R. H. Müller et al. (Müller, R H, Gohla, S, Keck, C M, State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm 2011; 78: 1-9).
Basically a certain total amount of energy input is required to reduce the size of the material to the nanorange. This total amount of energy can be generated by a low energy process over a long time, or a high energy process over a shorter time. Bead mill technology is low energy milling, whereas high pressure homogenization is high energy milling (pressures up to 1,500 or even up to 2,000 bar may be applied).
In the bead mill process, the material is suspended in a surfactant or stabilizer solution. The micrometer-sized suspension (i.e. macrosuspension) thus obtained is passed through a milling chamber containing fine milling beads (e.g. 1 mm in size or below). The milling beads are moved by an agitator, or by movement of the milling chamber itself. The material is ground to nanosize in between the moving milling beads, yielding a nanosuspension. The most pronounced disadvantages of a bead mill process are:    1. long milling times, up to hours and days (related to batch sizes of 1 kg to 100 kg);    2. potential product contamination due to the erosion of the milling beads during the long duration of the milling process; and    3. costs of the process due to the long processing times.
Therefore it would be desirable to have a process which is faster, minimizing production time and related costs.
During high pressure homogenization, the macrosuspension is milled by passing it through a homogenizer at high pressure. This may be a jet stream homogenizer (e.g. Microfluidizer by the company Microfluidics, Newton, Mass., USA (U.S. Pat. No. 6,337,092), or may be a piston gap homogenizer (e.g. APV Gaulin (Müller, R H, Becker R, Kruss B, Peters K, Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of dissolution, U.S. Pat. No. 5,858,410, WO96/14830, WO 01/03670).
The most pronounced disadvantages of high pressure homogenization are:    1. long production times because in many cases 20-50 passages (cycles) through the homogenizer are required; and    2. the high production pressure of up to 2,000 bar which can cause erosion from the machine (product contamination) or chemically decompose the processed active.
Therefore it is also desirable to be able to have shorter production times (reduced number of cycles) and to apply lower pressures.
The prior art describes attempts to obtain smaller sized nanocrystals or reducing the number of homogenization cycles by combining two production steps. Examples are the combination of spray drying and subsequent high pressure homogenization (DE 10 2005 011 786 A1, WO2006/094808) and freeze-drying and subsequent high pressure homogenization (DE 10 2005 017 777 A1, WO2006/108637). The disadvantages of these attempts are as follows:    1. The processes are relatively costly.    2. Spray drying, but especially lyophilisation, is time-consuming.    3. The number of cycles was reduced, but often still 5 (or even more) cycles are required.
Therefore, there is still a need for a more cost-efficient and faster production method. The present invention satisfies this need.